Vascular and valvular calcification, a prominent feature of chronic inflammatory disorders such as chronic renal disease, type II diabetes and dyslipidemia, associates with significant morbidity and mortality. Clinical, histological, and animal studies suggest that processes in vascular calcification are similar to those of bone remodeling (Hyder J A et al, American Journal of Epidemiology, 2009; Lieberman M et al, Arteriosclerosis, Thrombosis, and Vascular Biology, 2008; Bucay N et al, Genes & Development, 1998; Khosla S et al, Nature Medicine, 2011). Vascular calcification is an active, cell-regulated process in which vascular smooth muscle cells (SMCs) can lose the expression of their marker genes, acquire osteogenic markers, and deposit a mineralized bone-like matrix (Bostrom K I et al, Circulation Research, 2011). SMCs may play an important role in this process via transition toward an osteoblast-like state or releasing calcified matrix vesicles and microparticles.
Various therapeutic agents have been investigated to target cardiovascular calcification; these include statins (Aikawa E et al, Circulation, 2007; Monzack et al, ATVB, 2009; Osman L et al, Circulation, 2006; Rajamannan N M et al, Circulation, 2005; Wu Y W et al, Eur J Nucl Med Mol Imaging, 2012), bisphosphonate (Hartle J E et al, Am J Kidney Dis, 2012), phosphate binder (Di Iorio B et al, Clin J Am Soc Nephrol, 2012) and mineralocorticoid receptor antagonists (Gkizas S et al, Cardiovasc Pharma, 2010; Jaffe I Z et al, ATVB, 2007). However, beneficial effects of these drugs remain uncertain in the clinical setting (Gilmanov D, Inter. Cardiovasc Thor Surg, 2010). Thus, despite global clinical burden of cardiovascular calcification, no medical therapies are available.
Calcification in coronary arteries promotes heart attacks, which represent major health problems and economic burden in the United States. Calcification in carotid arteries associate with risk for stroke and dementia. Calcification in aortic valves causes aortic stenosis and heart failure. Especially, patients with mineral imbalance and calcium/phosphate disorders, including chronic renal disease, hemodyalysis and type II diabetes suffer from accelerated vascular and valvular calcification. For instance, arterio-venous shunts/grafts for hemodialysis in patients with chronic renal disease, vein grafts for peripheral arterial disease in diabetic patients, and saphenous vein bypass grafts for occluded coronary arteries in patients with metabolic disorders are often occluded within a year (vein graft failure). In the future, tissue engineered vascular and valvular implants in patients at metabolic risk may often fail. If the vein graft for peripheral arterial disease fails, the only options is an expensive redo surgery or stent implantation, or devastating amputation of the lower extremity. However, despite its high clinical and economic impact, no medical therapies are available to prevent or treat calcification.